Morpholylureas are a new class of potent and selective inhibitors of the type 5 17-ß-hydroxysteroid dehydrogenase (AKR1C3).
Bioorg Med Chem
; 22(3): 967-77, 2014 Feb 01.
Article
en En
| MEDLINE
| ID: mdl-24411201
ABSTRACT
Inhibitors of the aldo-keto reductase enzyme AKR1C3 are of interest as potential drugs for leukemia and hormone-related cancers. A series of non-carboxylate morpholino(phenylpiperazin-1-yl)methanones were prepared by palladium-catalysed coupling of substituted phenyl or pyridyl bromides with the known morpholino(piperazin-1-yl)methanone, and shown to be potent (IC50â¼100nM) and very isoform-selective inhibitors of AKR1C3. Lipophilic electron-withdrawing substituents on the phenyl ring were positive for activity, as was an H-bond acceptor on the other terminal ring, and the ketone moiety (as a urea) was essential. These structure-activity relationships are consistent with an X-ray structure of a representative compound bound in the AKR1C3 active site, which showed H-bonding between the carbonyl oxygen of the drug and Tyr55 and His117 in the 'oxyanion hole' of the enzyme, with the piperazine bridging unit providing the correct twist to allow the terminal benzene ring to occupy the lipophilic pocket and align with Phe311.
Palabras clave
AKR; Aldoketo reductase; COX; Computer aided drug design; Crystal structure; DCM; DIPEA; DMSO; Inhibitor; Morpholylureas; NADPH; NSAID; PBD; Protein Data Bank; TFA; aldoketo reductase; cyclo-oxygenase; dichloromethane; diisopropylethylamine; dimethyl sulfoxide; nicotinamide adenine dinucleotide phosphate; non-steroidal anti-inflammatory drugs; trifluoroacetic acid
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Hidroxiprostaglandina Deshidrogenasas
/
Inhibidores Enzimáticos
/
3-Hidroxiesteroide Deshidrogenasas
Idioma:
En
Revista:
Bioorg Med Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2014
Tipo del documento:
Article